Matrix metalloproteinase 13 modulates intestinal epithelial barrier integrity in inflammatory diseases by activating TNF

Several pathological processes, such as sepsis and inflammatory bowel disease (IBD), are associated with impairment of intestinal epithelial barrier. Here, we investigated the role of matrix metalloproteinase MMP13 in these diseases. We observed that MMP13(-/-) mice display a strong protection in LPS- and caecal ligation and puncture-induced sepsis. We could attribute this protection to reduced LPS-induced goblet cell depletion, endoplasmic reticulum stress, permeability and tight junction destabilization in the gut of MMP13(-/-) mice compared to MMP13(+/+) mice. Both in vitro and in vivo, we found that MMP13 is able to cleave pro-TNF into bioactive TNF. By LC-MS/MS, we identified three MMP13 cleavage sites, which proves that MMP13 is an alternative TNF sheddase next to the TNF converting enzyme TACE. Similarly, we found that the same mechanism was responsible for the observed protection of the MMP13(-/-) mice in a mouse model of DSS-induced colitis. We identified MMP13 as an important mediator in sepsis and IBD via the shedding of TNF. Hence, we propose MMP13 as a novel drug target for diseases in which damage to the gut is essential

Identification of a novel mechanism of blood-brain communication during peripheral inflammation via choroid plexus-derived extracellular vesicles

Here, we identified release of extracellular vesicles (EVs) by the choroid plexus epithelium (CPE) as a new mechanism of blood-brain communication. Systemic inflammation induced an increase in EVs and associated pro-inflammatory miRNAs, including miR-146a and miR-155, in the CSF. Interestingly, this was associated with an increase in amount of multivesicular bodies (MVBs) and exosomes per MVB in the CPE cells. Additionally, we could mimic this using LPS-stimulated primary CPE cells and choroid plexus explants. These choroid plexus-derived EVs can enter the brain parenchyma and are taken up by astrocytes and microglia, inducing miRNA target repression and inflammatory gene up-regulation. Interestingly, this could be blocked in vivo by intracerebroventricular (icv) injection of an inhibitor of exosome production. Our data show that CPE cells sense and transmit information about the peripheral inflammatory status to the central nervous system (CNS) via the release of EVs into the CSF, which transfer this pro-inflammatory message to recipient brain cells. Additionally, we revealed that blockage of EV secretion decreases brain inflammation, which opens up new avenues to treat systemic inflammatory diseases such as sepsis

Spatial filter issues

Experiments and calculations indicate that the threshold pressure in spatial filters for distortion of a transmitted pulse scales approximately as I{sup O.2} and (F{number_sign}){sup 2} over the intensity range from 10{sup 14} to 2xlO{sup 15} W/CM{sup 2} . We also demonstrated an interferometric diagnostic that will be used to measure the scaling relationships governing pinhole closure in spatial filters

The National Ignition Facility: The World's Largest Laser

The National Ignition Facility (NIF) is a 192-beam laser facility presently under construction at LLNL. When completed, NIF will be a 1.8-MJ, 500-TW ultraviolet laser system. Its missions are to obtain fusion ignition and to perform high energy density experiments in support of the U.S. nuclear weapons stockpile. Four of the NIF beams have been commissioned to demonstrate laser performance including target and beam alignment. During this time, NIF demonstrated on a single-beam basis that it will meet its performance goals and demonstrated its precision and flexibility for pulse shaping, pointing, timing and beam conditioning. It also performed four important experiments for Inertial Confinement Fusion and High Energy Density Science. Presently, the project is installing production hardware to complete the project in 2009 with the goal to begin ignition experiments in 2010. An integrated plan has been developed including the NIF operations, user equipment such as diagnostics and cryogenic target capability, and experiments and calculations to meet this goal

Third-harmonic performance of the Beamlet prototype laser

The Beamlet laser is a nearly full-scale, single-aperture prototype of the driver design for the National Ignition Facility (NIF). As part of a test and validation plan for the NIF design, Beamlet was recently equipped with final focusing optics and diagnostics for the purpose of evaluating integrated component performance and equivalent target-plane irradiance conditions at the 0.351-{mu}m output wavelength specified for NIF targets. A 37-cm aperture two-crystal converter scheme generates the third harmonic of the Nd:glass 1.053-{mu}m wavelength with high efficiency. The efficiency of the converter has been characterized and is reported, along with detailed measurements of the near-field and far-field UV irradiance distributions at operating conditions up to and exceeding red-line levels for the NIF. Dependences of observed beam quality on critical laser parameters including output power, B-integral, and spatial filtering are discussed and compared with numerical simulations

High fluence 1.05 {mu}m performance tests using 20 ns shaped pulses on the Beamlet prototype laser

Beamlet is a single beamline, nearly full scale physics prototype of the 192 beam Nd:Glass laser driver of the National Ignition Facility. It is used to demonstrate laser performance of the NIF multipass amplifier architecture. Initial system characterization tests have all been performed at pulse durations less than 10 ns. Pinhole closure and modulation at the end of long pulses are a significant concern for the operation of NIF. We recently demonstrated the generation, amplification and propagation of high energy pulses temporally shaped to mimic 20 ns long ignition pulse shapes at fluence levels exceeding the nominal NIF design requirements for Inertial Confinement Fusion by Indirect Drive. We also demonstrated the effectiveness of a new conical pinhole design used in the transport spatial filter to mitigate plasma closure effects and increase closure time to exceed the duration of the 20 ns long pulse

Involvement of the Choroid Plexus in the Pathogenesis of Niemann-Pick Disease Type C

Niemann-Pick type C (NPC) disease, sometimes called childhood Alzheimer's, is a rare neurovisceral lipid storage disease with progressive neurodegeneration leading to premature death. The disease is caused by loss-of-function mutations in the Npc1 or Npc2 gene which both result into lipid accumulation in the late endosomes and lysosomes. Since the disease presents with a broad heterogenous clinical spectrum, the involved disease mechanisms are still incompletely understood and this hampers finding an effective treatment. As NPC patients, who carry NPC1 mutations, have shown to share several pathological features with Alzheimer's disease (AD) and we and others have previously shown that AD is associated with a dysfunctionality of the blood-cerebrospinal fluid (CSF) barrier located at choroid plexus, we investigated the functionality of this latter barrier in NPC1 pathology. Using NPC1-/- mice, we show that despite an increase in inflammatory gene expression in choroid plexus epithelial (CPE) cells, the blood-CSF barrier integrity is not dramatically affected. Interestingly, we did observe a massive increase in autophagosomes in CPE cells and enlarged extracellular vesicles (EVs) in CSF upon NPC1 pathology. Additionally, we revealed that these EVs exert toxic effects on brain tissue, in vitro as well as in vivo. Moreover, we observed that EVs derived from the supernatant of NPC1-/- choroid plexus explants are able to induce typical brain pathology characteristics of NPC1-/-, more specifically microgliosis and astrogliosis. Taken together, our data reveal for the first time that the choroid plexus and CSF EVs might play a role in the brain-related pathogenesis of NPC1

Recent performance results of the National Ignition Facility Beamlet demonstration project

The laser driver for the National Ignition Facility will be a departure from previous inertial confinement fusion laser architecture of a master oscillator single pass power amplifier (MOPA) design. The laser will use multi-segment Nd:Glass amplifiers in a multipass cavity arrangement, which can be assembled into compact and cost effective arrays to deliver the required multi- megajoule energy to target. A single beam physics prototype, the Beamlet, has been in operation for over two years and has demonstrated the feasibility of this architecture. We present a short review of Beamlet`s performance and limitations based on beam quality both at its fundamental and frequency converted wavelengths of 1.053 and 0.351 {mu}m

Design and performance of the Beamlet laser third harmonic frequency converter

The Beamlet laser is a full-scale, single-aperture scientific prototype of the frequency-tripled Nd:glass laser for the proposed National Ignition Facility. At aperture sizes of 30 cm x 30 cm and 34 cm x 34 cm using potassium dihydrogen phosphate crystals of 32 cm x 32 cm and 37 cm x 37 cm, respectively, the authors have obtained up to 8.3 kJ of third harmonic energy at 70%--80% whole beam conversion efficiency